Project Summary The long-term goal of this line of research is to identify novel vaccine targets for malaria through improved understanding of cellular invasion by the parasite that causes this disease, Plasmodium. This research will also focus on the infectious stage of the parasite, the sporozoite, which has a complicated journey though both the mosquito and human body. Our overall objective in this project is to identify the precise mechanisms of interaction between Plasmodium and two contrasting host tissues, those of the mosquito salivary glands and the human liver. The determination of novel factors involved in cellular invasion by Plasmodium will allow the identification of novel vaccine targets for use in future translational studies. Our central hypothesis is that similar mechanisms involving host cell-derived epithelial factors are required for Plasmodium sporozoite invasion of both mosquito salivary glands and human hepatocytes. The rationale for this study is that determination of novel factors involved in cellular invasion by Plasmodium sporozoites will allow the identification of novel vaccine targets. We will test our hypothesis using rodent and human malaria models to address two specific Aims. In Aim 1, we will define the role of specific human liver cell-derived factors during invasion by Plasmodium. We will use gene knock-out in human liver cells and knock-out mouse models in order to investigate the effects of specific genes on Plasmodium invasion. In Aim 2, we will determine the extent to which specific proteins modified with attached sugar groups influence sporozoite invasion of the mosquito salivary glands. Again, we will primarily use gene-knock out studies combined with parasite invasion experiments to test for the involvement of several mosquito salivary gland genes during parasite invasion. The outcomes of this study are expected to be identification of the role specific liver proteins play in the sporozoite life cycle. The primary impact of our findings is anticipated to be identification of factors required for sporozoite invasion of host cells, the life-stage that is the most logical target for the development of an effective and affordable malaria vaccine.